ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are also discussed elsewhere in the labeling:Hypoglycemia [see Warnings and Precautions (5.3)] Medication Errors [see Warnings and Precautions (5.4)] Hypersensitivity [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Hypoglycemia [see Warnings and Precautions (5.3)] Medication Errors [see Warnings and Precautions (5.4)] Hypersensitivity [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Adverse reactions observed with HUMULIN include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. (6)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adverse Reactions from Clinical Studies or Postmarketing ReportsThe following additional adverse reactions have been identified during clinical studies or from postmarketing reports with use of HUMULIN R. Because some of these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or to establish causal relationship to drug exposure.. Adverse reactions associated with insulin initiation and glucose control intensificationIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy.. Hypersensitivity ReactionsSevere allergic reactions may include anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock.. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in HUMULIN R.. HypokalemiaHUMULIN can cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.. Injection Site ReactionsInjection site reactions may include injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass.. LipodystrophyAdministration of insulin subcutaneously, including HUMULIN R, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)].. Localized Cutaneous AmyloidosisLocalized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with sudden change to an unaffected injection site.. Medication ErrorsMedication errors in which other insulins have been accidentally substituted for HUMULIN have been identified during postapproval use.. Peripheral EdemaInsulin, including HUMULIN R, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. Weight GainWeight gain can occur with insulin therapy, including HUMULIN R, and has been attributed to the anabolic effects of insulin.. ImmunogenicityAs with all therapeutic peptides, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with HUMULIN is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed in animals.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of insulin, including HUMULIN R, is the regulation of glucose metabolism. Insulin lowers blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.. 12.2 Pharmacodynamics. The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual. With subcutaneous use, the pharmacologic effect of HUMULIN begins approximately 30 minutes (range: 10 to 75 minutes) after administration of doses in the 0.05 to 0.4 units/kg range (Figure 1). The effect is maximal at approximately hours (range: 20 minutes to hours) and terminates after approximately hours (range: to 14 hours). In study that administered 50 and 100 units doses subcutaneously to obese subjects, mean time of termination of effect was prolonged to approximately 18 hours (range approximately 12-24 hours).Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN (0.3 unit/kg) in Healthy Subjects.With intravenous use, the pharmacologic effect of HUMULIN begins at approximately 10 to 15 minutes and terminates at median time of approximately hours (range: to hours) after administration of doses in the range of 0.1 to 0.2 units/kg.The intravenous administration of HUMULIN was tested in 21 people with type diabetes. During the 6-hour assessment phase patients received intravenous HUMULIN at an initial dose of 0.5 units/hour, adjusted to maintain blood glucose concentrations near normoglycemia (100 to 160 mg/dL).The mean blood glucose levels during the assessment phase for patients on HUMULIN therapy are summarized below in Table 2. All patients achieved near normoglycemia during the 6-hour assessment phase. The average time (+- SE) required to attain near normoglycemia was 161 +- 14 minutes for HUMULIN R.Table 2: Mean Blood Glucose Concentrations (mg/dL) during Intravenous Infusions of HUMULIN Ra Results shown as mean +- Standard Deviation.Time from Start of Infusion (minutes)Mean Blood Glucose (mg/dL) Intravenousa 0220 +- 1130204 +- 1760193 +- 18120172 +- 28180153 +- 30240139 +- 24300131 +- 22360128 +- 18. Figure 1. 12.3 Pharmacokinetics. Absorption -- In healthy subjects given subcutaneous doses of HUMULIN ranging from 0.05 to 0.4 unit/kg, mean peak serum levels occurred between 36 to 150 minutes after dosing. After subcutaneous administration of single 12 unit dose (approximately 0.15 units/kg) to patients with type diabetes, the median peak serum level occurred at approximately hours (range: 20 minutes-6 hours). In study that administered 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) doses subcutaneously to healthy obese subjects, median peak serum levels were prolonged to approximately hours (range to hours). The absolute bioavailability after single subcutaneous injection of HUMULIN ranges from 48% to 89% in the 0.1 to 0.3 unit/kg dose range.. Distribution -- When HUMULIN is administered intravenously at doses of 0.1 or 0.2 unit/kg, the mean volume of distribution ranges between 0.32 to 0.67 L/kg.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Excretion -- After subcutaneous administration of HUMULIN doses in the 0.05-0.4 unit/kg dose range, the median apparent half-life is approximately 1.5 hours (range: 40 minutes-7 hours). Mean apparent half-life of HUMULIN after subcutaneous administration of higher doses (50 and 100 units) to healthy obese subjects was approximately 3.6 hours (range= 1.6-8.6 hours).When administered intravenously, HUMULIN had mean half-life of approximately 20 minutes at 0.1 unit/kg dose and hour at 0.2 unit/kg dose.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. HUMULIN is contraindicated:during episodes of hypoglycemiain patients with hypersensitivity to HUMULIN or any of its excipients.. during episodes of hypoglycemia. in patients with hypersensitivity to HUMULIN or any of its excipients.. Do not use during episodes of hypoglycemia. (4)Do not use in patients with hypersensitivity to HUMULIN or any of its excipients. (4). Do not use during episodes of hypoglycemia. (4). Do not use in patients with hypersensitivity to HUMULIN or any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. HUMULIN (insulin human injection) is short-acting human insulin for subcutaneous or intravenous use. HUMULIN is produced by recombinant DNA technology utilizing non-pathogenic laboratory strain of Escherichia coli. HUMULIN is regular human insulin and has the empirical formula C257H383N65O77S6 with molecular weight of 5808.HUMULIN is sterile, aqueous, clear, and colorless solution. HUMULIN contains 100 units of insulin in each milliliter. Each milliliter of HUMULIN also contains glycerin 16 mg, metacresol 2.5 mg, endogenous zinc (approximately 0.015 mg/100 units,) and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. See Full Prescribing Information for important administration instructions. (2.1)Subcutaneous injection: inject subcutaneously 30 minutes before meal into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2)Intravenous infusion: administer intravenously ONLY under medical supervision at concentrations from 0.1 unit/mL to unit/mL in infusion systems containing 0.9% sodium chloride. (2.2)Individualize dose based on route of administration, metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3)HUMULIN given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. (2.3)Do not mix with insulin preparations other than HUMULIN(R) N. (2.5). See Full Prescribing Information for important administration instructions. (2.1). Subcutaneous injection: inject subcutaneously 30 minutes before meal into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2). Intravenous infusion: administer intravenously ONLY under medical supervision at concentrations from 0.1 unit/mL to unit/mL in infusion systems containing 0.9% sodium chloride. (2.2). Individualize dose based on route of administration, metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3). HUMULIN given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. (2.3). Do not mix with insulin preparations other than HUMULIN(R) N. (2.5). 2.1 Important Administration Instructions. Always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.4)].Inspect HUMULIN visually before use. It should appear clear and colorless. Do not use HUMULIN if particulate matter or coloration is seen.. Always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.4)].. Inspect HUMULIN visually before use. It should appear clear and colorless. Do not use HUMULIN if particulate matter or coloration is seen.. 2.2 Route of Administration. Subcutaneous InjectionInject HUMULIN subcutaneously approximately 30 minutes before meals into the thigh, upper arm, abdomen, or buttocks.Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].Intravenous AdministrationAdminister HUMULIN intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to reduce the risk of hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6), How Supplied/Storage and Handling (16.3)].For intravenous use, HUMULIN should be used at concentrations from 0.1 unit/mL to unit/mL in infusion systems containing 0.9% sodium chloride.. Inject HUMULIN subcutaneously approximately 30 minutes before meals into the thigh, upper arm, abdomen, or buttocks.. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. Administer HUMULIN intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to reduce the risk of hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6), How Supplied/Storage and Handling (16.3)].. For intravenous use, HUMULIN should be used at concentrations from 0.1 unit/mL to unit/mL in infusion systems containing 0.9% sodium chloride.. 2.3 Dosing Instructions. Individualize and adjust the dosage of HUMULIN based on the route of administration, the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.HUMULIN given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (e.g., macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness [see Warnings and Precautions (5.2, 5.3), Use in Specific Populations (8.6, 8.7)].Dosage adjustment may be needed when switching from another insulin to HUMULIN [see Warnings and Precautions (5.2)].. Individualize and adjust the dosage of HUMULIN based on the route of administration, the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.. HUMULIN given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (e.g., macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness [see Warnings and Precautions (5.2, 5.3), Use in Specific Populations (8.6, 8.7)].. Dosage adjustment may be needed when switching from another insulin to HUMULIN [see Warnings and Precautions (5.2)].. 2.4 Dosage Adjustment due to Drug Interactions. Dosage adjustment may be needed when HUMULIN is co-administered with certain drugs [see Drug Interactions (7)].. Dosage adjustment may be needed when HUMULIN is co-administered with certain drugs [see Drug Interactions (7)].. 2.5 Instructions for Mixing with Other Insulins for Subcutaneous Injection. Do not mix HUMULIN with insulin preparations other than HUMULIN N.To mix HUMULIN and HUMULIN N, draw HUMULIN into the syringe first. Inject immediately after mixing.. Do not mix HUMULIN with insulin preparations other than HUMULIN N.. To mix HUMULIN and HUMULIN N, draw HUMULIN into the syringe first. Inject immediately after mixing.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. HUMULIN is indicated to improve glycemic control in pediatric patients with diabetes mellitus.The dosage of HUMULIN must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. HUMULIN injection is 100 units per mL (U-100), clear and colorless solution available as:10 mL multiple-dose vial3 mL multiple-dose vial. 10 mL multiple-dose vial. mL multiple-dose vial. Injection: HUMULIN 100 units per mL (U-100) is available as:10 mL multiple-dose vial (3)3 mL multiple-dose vial (3). 10 mL multiple-dose vial (3). mL multiple-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 1: Clinically Significant Drug Interactions with HUMULIN RDrugs that May Increase the Risk of HypoglycemiaDrugs:Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibioticsIntervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.Drugs that May Decrease the Blood Glucose Lowering Effect of HUMULIN RDrugs:Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN RDrugs:Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.Drugs that May Blunt Signs and Symptoms of HypoglycemiaDrugs:Beta-blockers, clonidine, guanethidine, and reserpineIntervention:Increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.. Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7)Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones (7)Drugs that may increase or decrease the blood glucose lowering effect: Alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7)Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7). Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7). Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones (7). Drugs that may increase or decrease the blood glucose lowering effect: Alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7). Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Elderly patients using HUMULIN may be at increased risk of hypoglycemia due to co-morbid disease [see Warnings and Precautions (5.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. HUMULIN injection is 100 units per mL (U-100), clear and colorless solution available as:10 mL multiple-dose vialNDC 0002-8215-013 mL multiple-dose vialNDC 0002-8215-17Patients using HUMULIN vials must never share needles or syringes with another person.. 16.2 Storage and Handling. Protect from heat and light. Do not freeze. Do not use HUMULIN after the expiration date printed on the label or if it has been frozen.Table 3. Storage Conditions and Expiration Dates for HUMULIN RNot In-Use (Unopened) Refrigerated(36 to 46F [2 to 8C])Not In-Use (Unopened) Room Temperature(below 86F [30C])In-Use (Opened)Refrigerated or Room Temperature10 mL multiple-dose vial3 mL multiple-dose vialUntil expiration date31 days31 days. 16.3 Admixture for Intravenous Administration. Intravenous infusion bags prepared with HUMULIN are stable when stored in refrigerator (36 to 46F [2 to 8C]) for 48 hours and then may be used at room temperature for up to an additional 48 hours [see Dosage and Administration (2.2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. HUMULIN is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.. HUMULIN(R) is short-acting human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Never Share Needles or Syringes between PatientsAdvise patients using HUMULIN vials not to share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. Hyperglycemia or HypoglycemiaInform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia [see Warnings and Precautions (5.3)].Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].. Medication ErrorsInstruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with HUMULIN R. Inform patients on the symptoms of hypersensitivity reactions and to seek medical attention if they occur [see Warnings and Precautions (5.5)].. Literature Revised: November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1997, 2019, Eli Lilly and Company. All rights reserved.LINR100-0003-USPI-20191115.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseHumulin(R)(HU-mu-lin) Rinsulin human injectionmultiple-dose vial (100 units/mL)Read the Instructions for Use before you start taking HUMULIN and each time you get new vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Do not share your syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.Supplies needed to give your injectiona multiple-dose HUMULIN(R) viala U-100 insulin syringe and needle2 alcohol swabs1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.VialSyringePreparing the DoseWash your hands with soap and water.Check the HUMULIN label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.Do not use HUMULIN past the expiration date printed on the label or 31 days after you first use it.Always use new syringe or needle for each injection to help make sure the syringe needle is sterile and to prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Step 1:Check the insulin. HUMULIN solution should look clear and colorless. Do not use HUMULIN if it looks cloudy, thick, slightly colored, or if you see particles in the solution.Step 2:If you are using new HUMULIN vial, flip off the plastic protective Cap, but do not remove the Rubber Stopper.Step 3:Wipe the Rubber Stopper with an alcohol swab.Step 4: Hold the syringe with the needle pointing up. Pull down on the Plunger until the tip of the Plunger reaches the line for the number of units for your prescribed dose.(Example Dose: 20 units shown)Step 5:Push the needle through the Rubber Stopper of the vial.Step 6:Push the Plunger all the way in. This puts air into the vial.Step 7:Turn the vial and syringe upside down and slowly pull the plunger down until the tip is few units past the line for your prescribed dose.(Example Dose: 20 units Plunger is shown at 24 units)If there are air bubbles in the syringe, tap the syringe gently few times to let any air bubbles rise to the top.Step 8:Slowly push the Plunger up until the tip reaches the line for your prescribed dose.Check to make sure that you have the right dose.(Example Dose: 20 units shown)Step 9:Pull the syringe out of the vials Rubber Stopper.If you use HUMULIN with HUMULIN N:HUMULIN is the only type of insulin that can be mixed with HUMULIN R. Do not mix HUMULIN with any other type of insulin.HUMULIN should be drawn up into the syringe first, before you draw up Humulin N. Talk to your healthcare provider if you are not sure about the right way to mix HUMULIN and HUMULIN N.Give your injection right away.Giving your InjectionInject your insulin exactly as your healthcare provider has shown you.Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Step 10:Choose your injection site.HUMULIN is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms.Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.Step 11:Insert the needle into your skin.Step 12:Push down on the Plunger to inject your dose.The needle should stay in your skin for at least seconds to make sure you have injected all of your insulin dose.Step 13:Pull the needle out of your skin.You may see drop of insulin at the needle tip. This is normal and does not affect the dose you received.If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.Do not recap the needle. Recapping the needle can lead to needle stick injury.Disposing of used needles and syringes:Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak resistant, and-properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.How should store HUMULIN RAll unopened vials:Store all unopened vials in the refrigerator at 36 to 46F (2 to 8C).Do not freeze. Do not use if it has been frozen.Keep away from heat and out of direct light.Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.Unopened vials should be thrown away after 31 days if they are stored at room temperatureAfter vials have been opened:Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 31 days.Keep away from heat and out of direct light.Throw away all opened vials after 31 days, even if there is still insulin left in the vial.General information about the safe and effective useKeep HUMULIN vials, syringes, needles, and all medicines out of the reach of children.Always use new syringe or needle for each injection.Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.If you have any questions or problems with your HUMULIN, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN and insulin, go to www.humulin.com.Scan this code to launch the humulin.com websiteThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Humulin(R) is trademark of Eli Lilly and Company.Instructions for Use revised: November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1997, 2019, Eli Lilly and Company. All rights reserved.LINR100VL-0003-IFU-20191115. multiple-dose HUMULIN(R) vial. U-100 insulin syringe and needle. alcohol swabs. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water.. Check the HUMULIN label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. Do not use HUMULIN past the expiration date printed on the label or 31 days after you first use it.. Always use new syringe or needle for each injection to help make sure the syringe needle is sterile and to prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. HUMULIN is the only type of insulin that can be mixed with HUMULIN R. Do not mix HUMULIN with any other type of insulin.. HUMULIN should be drawn up into the syringe first, before you draw up Humulin N. Talk to your healthcare provider if you are not sure about the right way to mix HUMULIN and HUMULIN N.. Give your injection right away.. Inject your insulin exactly as your healthcare provider has shown you.. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.. Do not inject where the skin has pits, is thickened, or has lumps.. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. You may see drop of insulin at the needle tip. This is normal and does not affect the dose you received.. If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.. Do not recap the needle. Recapping the needle can lead to needle stick injury.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak resistant, and-properly labeled to warn of hazardous waste inside the container. -made of heavy-duty plastic,. -can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. -upright and stable during use,. -leak resistant, and. -properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Store all unopened vials in the refrigerator at 36 to 46F (2 to 8C).. Do not freeze. Do not use if it has been frozen.. Keep away from heat and out of direct light.. Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.. Unopened vials should be thrown away after 31 days if they are stored at room temperature. Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 31 days.. Keep away from heat and out of direct light.. Throw away all opened vials after 31 days, even if there is still insulin left in the vial.. Keep HUMULIN vials, syringes, needles, and all medicines out of the reach of children.. Always use new syringe or needle for each injection.. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN R, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of insulin, including HUMULIN R, is the regulation of glucose metabolism. Insulin lowers blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed in animals.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately [see Warnings and Precautions (5.3, 5.6)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON HUMULIN U-100 Vial 10 mL 1ct. NDC 0002-8215-01HI-21010 mL100 units per mLHumulin(R) RREGULARinsulin human injectionU-100www.lilly.comLilly. PACKAGE CARTON HUMULIN U-100 Vial 10 mL 1ct.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual. With subcutaneous use, the pharmacologic effect of HUMULIN begins approximately 30 minutes (range: 10 to 75 minutes) after administration of doses in the 0.05 to 0.4 units/kg range (Figure 1). The effect is maximal at approximately hours (range: 20 minutes to hours) and terminates after approximately hours (range: to 14 hours). In study that administered 50 and 100 units doses subcutaneously to obese subjects, mean time of termination of effect was prolonged to approximately 18 hours (range approximately 12-24 hours).Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN (0.3 unit/kg) in Healthy Subjects.With intravenous use, the pharmacologic effect of HUMULIN begins at approximately 10 to 15 minutes and terminates at median time of approximately hours (range: to hours) after administration of doses in the range of 0.1 to 0.2 units/kg.The intravenous administration of HUMULIN was tested in 21 people with type diabetes. During the 6-hour assessment phase patients received intravenous HUMULIN at an initial dose of 0.5 units/hour, adjusted to maintain blood glucose concentrations near normoglycemia (100 to 160 mg/dL).The mean blood glucose levels during the assessment phase for patients on HUMULIN therapy are summarized below in Table 2. All patients achieved near normoglycemia during the 6-hour assessment phase. The average time (+- SE) required to attain near normoglycemia was 161 +- 14 minutes for HUMULIN R.Table 2: Mean Blood Glucose Concentrations (mg/dL) during Intravenous Infusions of HUMULIN Ra Results shown as mean +- Standard Deviation.Time from Start of Infusion (minutes)Mean Blood Glucose (mg/dL) Intravenousa 0220 +- 1130204 +- 1760193 +- 18120172 +- 28180153 +- 30240139 +- 24300131 +- 22360128 +- 18. Figure 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption -- In healthy subjects given subcutaneous doses of HUMULIN ranging from 0.05 to 0.4 unit/kg, mean peak serum levels occurred between 36 to 150 minutes after dosing. After subcutaneous administration of single 12 unit dose (approximately 0.15 units/kg) to patients with type diabetes, the median peak serum level occurred at approximately hours (range: 20 minutes-6 hours). In study that administered 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) doses subcutaneously to healthy obese subjects, median peak serum levels were prolonged to approximately hours (range to hours). The absolute bioavailability after single subcutaneous injection of HUMULIN ranges from 48% to 89% in the 0.1 to 0.3 unit/kg dose range.. Distribution -- When HUMULIN is administered intravenously at doses of 0.1 or 0.2 unit/kg, the mean volume of distribution ranges between 0.32 to 0.67 L/kg.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Excretion -- After subcutaneous administration of HUMULIN doses in the 0.05-0.4 unit/kg dose range, the median apparent half-life is approximately 1.5 hours (range: 40 minutes-7 hours). Mean apparent half-life of HUMULIN after subcutaneous administration of higher doses (50 and 100 units) to healthy obese subjects was approximately 3.6 hours (range= 1.6-8.6 hours).When administered intravenously, HUMULIN had mean half-life of approximately 20 minutes at 0.1 unit/kg dose and hour at 0.2 unit/kg dose.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7% and has been reported to be as high as 20-25% in women with HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human DataWhile available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)11/2019Warnings and Precautions (5.2)11/2019.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: November 2019Patient InformationHumulin(R)(HU-mu-lin) Rinsulin human injection(100 units per mL)Do not share your syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.What is Humulin RHumulin is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.Who should not use Humulin RDo not use Humulin if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to human insulin or any of the ingredients in Humulin R. See the end of this Patient Information leaflet for complete list of ingredients in Humulin R.What should tell my healthcare provider before using Humulin RBefore using Humulin R, tell your healthcare provider about all your medical conditions including, if you:have liver or kidney problems.take other medicines, especially ones called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Humulin R.are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.are breast-feeding or plan to breastfeed. HUMULIN may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN R.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Before you start using Humulin R, talk to your healthcare provider about low blood sugar and how to manage it. How should use Humulin RRead the detailed Instructions for Use that comes with your Humulin R.Use Humulin exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Humulin to use and when to use it.Use Humulin 30 minutes before eating meal.Know the type, strength, and amount of insulin you use. Do not change the type, or amount of insulin you use unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you use different types of insulin.Check your insulin label each time you give your injection to make sure you are using the correct insulin.Inject Humulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, buttocks or stomach area (abdomen). Do not inject Humulin into your vein (intravenously) or muscle (intramuscularly).-Do not mix Humulin with any other insulin except Humulin(R) N. If Humulin is mixed with Humulin N, Humulin should be drawn into the syringe first. Inject immediately after mixing. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.-Do not use the exact same spot for each injection.-Do not inject where the skin has pits, is thickened, or has lumps.-Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.Keep Humulin and all medicines out of reach of children.Your dose of Humulin may need to change because of: change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take What should avoid while using Humulin RWhile using Humulin do not: drive or operate heavy machinery, until you know how Humulin affects you.drink alcohol or use prescription or over-the-counter medicines that contain alcohol. What are the possible side effects of Humulin RHumulin may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:-dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.-Your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth. severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction:-a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.low potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with Humulin may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with Humulin R. Your healthcare provider should monitor you closely while you are taking TZDs with Humulin R. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:-shortness of breath, swelling of your ankles or feet, sudden weight gain Treatment with TZDs and Humulin may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units of Humulin that your healthcare provider has prescribed for you.trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. The most common side effects of Humulin include:low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy), weight gain, swelling (edema) in hands or feet, itching and rash. These are not all of the possible side effects of Humulin R. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General Information about the safe and effective use of Humulin RMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Humulin for condition for which it was not prescribed. Do not give Humulin to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about Humulin R. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Humulin that is written for healthcare providers. For more information go to www.humulin.com or call 1-800-LillyRx (1-800-545-5979).What are the ingredients in Humulin RActive Ingredient: human insulin Inactive ingredients: glycerin, metacresol, water for injection, sodium hydroxide and hydrochloric acid. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA For more information about Humulin go to www.humulin.com. Copyright (C) 2007, 2019, Eli Lilly and Company. All rights reserved.LINR100-0003-PPI-20191115. Humulin is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to human insulin or any of the ingredients in Humulin R. See the end of this Patient Information leaflet for complete list of ingredients in Humulin R.. have liver or kidney problems.. take other medicines, especially ones called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Humulin R.. are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. are breast-feeding or plan to breastfeed. HUMULIN may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN R.. Read the detailed Instructions for Use that comes with your Humulin R.. Use Humulin exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Humulin to use and when to use it.. Use Humulin 30 minutes before eating meal.. Know the type, strength, and amount of insulin you use. Do not change the type, or amount of insulin you use unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you use different types of insulin.. Check your insulin label each time you give your injection to make sure you are using the correct insulin.. Inject Humulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, buttocks or stomach area (abdomen). Do not inject Humulin into your vein (intravenously) or muscle (intramuscularly).-Do not mix Humulin with any other insulin except Humulin(R) N. If Humulin is mixed with Humulin N, Humulin should be drawn into the syringe first. Inject immediately after mixing. -Do not mix Humulin with any other insulin except Humulin(R) N. If Humulin is mixed with Humulin N, Humulin should be drawn into the syringe first. Inject immediately after mixing.. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.-Do not use the exact same spot for each injection.-Do not inject where the skin has pits, is thickened, or has lumps.-Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. -Do not use the exact same spot for each injection.. -Do not inject where the skin has pits, is thickened, or has lumps.. -Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.. change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take. drive or operate heavy machinery, until you know how Humulin affects you.. drink alcohol or use prescription or over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:-dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.-Your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth. -dizziness or lightheadedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood changes, hunger.. -Your healthcare provider may prescribe glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.. severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of severe allergic reaction:-a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.. -a rash over your whole body, have trouble breathing, fast heartbeat, or sweating.. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with Humulin may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with Humulin R. Your healthcare provider should monitor you closely while you are taking TZDs with Humulin R. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:-shortness of breath, swelling of your ankles or feet, sudden weight gain -shortness of breath, swelling of your ankles or feet, sudden weight gain. severe hypoglycemia needing hospitalization or emergency room care, and be sure to tell the hospital staff the units of Humulin that your healthcare provider has prescribed for you.. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. low blood sugar (hypoglycemia), allergic reactions including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy), weight gain, swelling (edema) in hands or feet, itching and rash.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Instructions. Always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.4)].Inspect HUMULIN visually before use. It should appear clear and colorless. Do not use HUMULIN if particulate matter or coloration is seen.. Always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.4)].. Inspect HUMULIN visually before use. It should appear clear and colorless. Do not use HUMULIN if particulate matter or coloration is seen.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Protect from heat and light. Do not freeze. Do not use HUMULIN after the expiration date printed on the label or if it has been frozen.Table 3. Storage Conditions and Expiration Dates for HUMULIN RNot In-Use (Unopened) Refrigerated(36 to 46F [2 to 8C])Not In-Use (Unopened) Room Temperature(below 86F [30C])In-Use (Opened)Refrigerated or Room Temperature10 mL multiple-dose vial3 mL multiple-dose vialUntil expiration date31 days31 days.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7% and has been reported to be as high as 20-25% in women with HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human DataWhile available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.. 8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN R, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.. 8.4 Pediatric Use. HUMULIN is indicated to improve glycemic control in pediatric patients with diabetes mellitus.The dosage of HUMULIN must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].. 8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Elderly patients using HUMULIN may be at increased risk of hypoglycemia due to co-morbid disease [see Warnings and Precautions (5.3)].. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share needles or syringes with another person. (5.1)Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2)Hypoglycemia: May be life-threatening. Increase frequency of blood glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment or with hypoglycemia unawareness. (5.3)Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4)Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R, monitor, and treat if indicated. (5.5)Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. (5.6)Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.7). Never share needles or syringes with another person. (5.1). Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2). Hypoglycemia: May be life-threatening. Increase frequency of blood glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment or with hypoglycemia unawareness. (5.3). Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4). Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R, monitor, and treat if indicated. (5.5). Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. (5.6). Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.7). 5.1 Never Share Needles or Syringes between Patients. Patients using HUMULIN vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen. Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)]. Make any changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type diabetes, adjustments in concomitant anti-diabetic medications may be needed.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction of all insulins, including HUMULIN R. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of HUMULIN may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)].Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].. Risk Mitigation Strategies for HypoglycemiaPatients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.. 5.4 Hypoglycemia Due to Medication Errors. Accidental mix-ups between HUMULIN and other insulins have been reported. To avoid medication errors between HUMULIN and other insulins, instruct patients to always check the insulin label before each injection.. 5.5 Hypersensitivity and Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with HUMULIN [see Adverse Reactions (6)]. If hypersensitivity reactions occur, discontinue HUMULIN R; treat per standard of care and monitor until symptoms and signs resolve. HUMULIN is contraindicated in patients who have had hypersensitivity reaction to HUMULIN or its excipients [see Contraindications (4)].. 5.6 Hypokalemia. All insulin products, including HUMULIN R, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMULIN R, and PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.